Pharmacogenetics of Antidepressant Drugs
While antidepressants are widely used to treat mood and anxiety disorders, only half of the patients will respond to antidepressant treatment and only one-third of patients experience a full remission of symptoms. The identification of genetic biomarkers that predict antidepressant-treatment response can improve current clinical practice. This is an emerging field known as pharmacogenetics, which comprises of genetic studies on both the pharmacokinetics and pharmacodynamics of treatment response. Recent studies on antidepressant-treatment response have focused on both aspects of pharmacogenetics research, identifying new candidate genes that may predict better treatment response for patients. This paper reviews recent findings on the pharmacogenetics of antidepressant drugs and future clinical applications. Ultimately, these studies should lead to the use of genetic testing to guide the use of antidepressants in clinical practice.
While antidepressant drugs are widely prescribed to treat depression and anxiety disorders, only one-third of drug-treated patients exhibit a beneficial therapeutic response. Response and tolerability to medication are highly variable, with some patients responding to one treatment but not another. There are several potential explanations for these poor drug-response rates, including clinical heterogeneity and diagnostic uncertainty, environmental and social factors, and genetics factors. If it were possible to isolate variables that could predict a greater likelihood of positive response to the medication, it would be possible to use the medication with greater certainty and efficiency. This forms the basis of much of the contemporary effort in the field of personalized medicine. Thus, a critical question remains: for which patients will antidepressant therapy have the greatest benefit?
Early studies suggested that specific clinical phenotypes, such as melancholic or anxious depression, might predict differential responses to antidepressants; however, the clinical phenotypes were often variable and difficult to translate into clinical practice. Pharmacogenetics, which is the identification and development of genetic biomarkers that predict therapeutic response and the risk of side effects, takes a different approach to ultimately help the practitioner in choosing effective and safe treatment for patients suffering from psychiatric disorders.
The discovery of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) in the 1950s spurred on research into developing new antidepressant medications with a better safety and tolerability profile. Following a serotonin (5-HT) hypothesis of depression, the selective 5-HT reuptake inhibitors (SSRIs) were discovered to be more effective antidepressants, with their improved safety and tolerability profile. More recently, dual-acting antidepressants such as 5-HT–norepinephrine (NE) reuptake inhibitors (SNRIs) have presented clinicians with a wider range of antidepressants that are effective, safe and easy to prescribe. Currently, SSRIs are usually the first method of treatment, with dual-acting TCAs and SNRIs used as second-line treatment.
There has been a recent increase in the use of antidepressants across the USA, particularly for major depressive disorder (MDD), but also for other disorders such as anxiety, bipolar disorder and adjustment-related disorders. Current clinical guidelines suggest antidepressants, particularly SSRIs, as treatment for anxiety disorders, chronic pain and bipolar depression. With MDD affecting 10–15% of the population and anxiety disorders affecting approximately 25% of the population, a large percentage of the population use antidepressants for pharmacotherapy. However, response and tolerability to medication are highly variable, with some patients responding to one treatment but not another. Pharmacogenetics research attempts to use genetic factors to predict some of the variability in treatment response. Early studies showed a correlation between relatives with depression in antidepressant-treatment responses. One small study found pairs of related people with depression responded equally well to antidepressants, while another study found that depressed probands and depressed relatives had favorable responses to the same class of antidepressants. Such studies indicated a role for genetics in antidepressant-treatment outcome, spurring on pharmacogenetic research in this field. This article will review current pharmacogenetic studies of antidepressants in mood and anxiety disorders and discuss the clinical future of the current research.
Abstract and Introduction
Abstract
While antidepressants are widely used to treat mood and anxiety disorders, only half of the patients will respond to antidepressant treatment and only one-third of patients experience a full remission of symptoms. The identification of genetic biomarkers that predict antidepressant-treatment response can improve current clinical practice. This is an emerging field known as pharmacogenetics, which comprises of genetic studies on both the pharmacokinetics and pharmacodynamics of treatment response. Recent studies on antidepressant-treatment response have focused on both aspects of pharmacogenetics research, identifying new candidate genes that may predict better treatment response for patients. This paper reviews recent findings on the pharmacogenetics of antidepressant drugs and future clinical applications. Ultimately, these studies should lead to the use of genetic testing to guide the use of antidepressants in clinical practice.
Introduction
While antidepressant drugs are widely prescribed to treat depression and anxiety disorders, only one-third of drug-treated patients exhibit a beneficial therapeutic response. Response and tolerability to medication are highly variable, with some patients responding to one treatment but not another. There are several potential explanations for these poor drug-response rates, including clinical heterogeneity and diagnostic uncertainty, environmental and social factors, and genetics factors. If it were possible to isolate variables that could predict a greater likelihood of positive response to the medication, it would be possible to use the medication with greater certainty and efficiency. This forms the basis of much of the contemporary effort in the field of personalized medicine. Thus, a critical question remains: for which patients will antidepressant therapy have the greatest benefit?
Early studies suggested that specific clinical phenotypes, such as melancholic or anxious depression, might predict differential responses to antidepressants; however, the clinical phenotypes were often variable and difficult to translate into clinical practice. Pharmacogenetics, which is the identification and development of genetic biomarkers that predict therapeutic response and the risk of side effects, takes a different approach to ultimately help the practitioner in choosing effective and safe treatment for patients suffering from psychiatric disorders.
The discovery of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) in the 1950s spurred on research into developing new antidepressant medications with a better safety and tolerability profile. Following a serotonin (5-HT) hypothesis of depression, the selective 5-HT reuptake inhibitors (SSRIs) were discovered to be more effective antidepressants, with their improved safety and tolerability profile. More recently, dual-acting antidepressants such as 5-HT–norepinephrine (NE) reuptake inhibitors (SNRIs) have presented clinicians with a wider range of antidepressants that are effective, safe and easy to prescribe. Currently, SSRIs are usually the first method of treatment, with dual-acting TCAs and SNRIs used as second-line treatment.
There has been a recent increase in the use of antidepressants across the USA, particularly for major depressive disorder (MDD), but also for other disorders such as anxiety, bipolar disorder and adjustment-related disorders. Current clinical guidelines suggest antidepressants, particularly SSRIs, as treatment for anxiety disorders, chronic pain and bipolar depression. With MDD affecting 10–15% of the population and anxiety disorders affecting approximately 25% of the population, a large percentage of the population use antidepressants for pharmacotherapy. However, response and tolerability to medication are highly variable, with some patients responding to one treatment but not another. Pharmacogenetics research attempts to use genetic factors to predict some of the variability in treatment response. Early studies showed a correlation between relatives with depression in antidepressant-treatment responses. One small study found pairs of related people with depression responded equally well to antidepressants, while another study found that depressed probands and depressed relatives had favorable responses to the same class of antidepressants. Such studies indicated a role for genetics in antidepressant-treatment outcome, spurring on pharmacogenetic research in this field. This article will review current pharmacogenetic studies of antidepressants in mood and anxiety disorders and discuss the clinical future of the current research.
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